Nirmatrelvir-ritonavir (NMV/r) is now being used to treat high-risk patients with mild to moderate COVID-19. This article provides advice to clinicians regarding recognition of medications likely to interact with NMV/r and suggests approaches to managing such drug-drug interactions. An algorithm is provided to assist in decision making

Back, D.

Boffito, M.

Boyle, A.

Burger, D.

Flexner, C.

Gibbons, S.

Khoo, S.

Kuritzkes, D. R.

Marra, F.

Marzolini, C.

Pozniak, A.

Waters, L.

English

PubMed

Item does not contain fulltextNirmatrelvir–ritonavir (NMV/r) is now being used to treat high-risk patients with mild to moderate COVID-19. This article provides advice to clinicians regarding recognition of medications likely to interact with NMV/r and suggests approaches to managing such drug–drug interactions. An algorithm is provided to assist in decision making

Kuritzkes, D.R.

Burger, D.M.

Radboud Repository

Prescribing Nirmatrelvir-Ritonavir: How to Recognize and Manage Drug-Drug Interactions

Serveur académique lausannois

Prescribing Nirmatrelvir–Ritonavir: How to Recognize and ManageDrug–Drug InteractionsCatia Marzolini, PharmD, PhD; Daniel R. Kuritzkes, MD; Fiona Marra, PharmD; Alison Boyle, PharmD; Sara Gibbons, MPhil;Charles Flexner, MD; Anton Pozniak, MD; Marta Boffito, MD, PhD; Laura Waters, MD; David Burger, PharmD, PhD;David Back, PhD; and Saye Khoo, MDNirmatrelvir–ritonavir (NMV/r) is increasingly availablefor use in high-risk patients with mild to moderateCOVID-19 (1) who are likely to be receiving other medi-cations. The use of ritonavir to boost plasma concentra-tions of nirmatrelvir through inhibition of cytochromeP450 (CYP) 3A4 confers a high potential for clinically sig-nificant drug–drug interactions (DDIs). Although HIV spe-cialists have more than 2 decades of experience withritonavir boosting (2), the 5-day treatment with oral NMV/rwill be primarily prescribed by practitioners lacking suchexperience. The most important restriction to use of NMV/rwill be DDIs. Moreover, limited management options(home isolation, accessing investigations, short windowfor intervention, and difficulties of dose adjustment) andthe risk for unrecognized DDIs or their toxicities presentchallenges. Treatment guidance must be clear, simple,unambiguous, and pragmatic, balancing the risk for harmfrom DDIs with a short course of ritonavir against unneces-sary denial of NMV/r treatment. We brought togetherexpert clinicians and antiviral pharmacologists from Europeand North America to synthesize evidence-based, prag-matic recommendations for managing DDIs with NMV/r.Safe prescribing of NMV/r requires full medication rec-onciliation, including over-the-counter medicines, herbals,and recreational drugs. Interactions between NMV/r andcomedications can be screened using specialized resour-ces, such as the National Institutes of Health COVID-19treatment guidelines (3) or the University of Liverpool'swebsite on COVID-19 drug interactions (4). Becausethese resources are comprehensive but not exhaustive,it is essential to understand when to anticipate a clini-cally relevant DDI with NMV/r by considering the meta-bolic pathways of co-administered medications.RECOGNITION OF MEDICATIONS LIKELY TOSIGNIFICANTLY INTERACT WITH NMV/RRitonavir inhibition of CYP3A4, and also the trans-porter P-glycoprotein, means that significant DDIs canbe expected with comedications that are predominantlymetabolized by CYP3A4 and/or have a narrow therapeu-tic index (such as tacrolimus) or are sensitive substratesof P-glycoprotein (such as digoxin). The contribution ofCYP3A4 to the overall disposition of a drug determinesthe magnitude of a DDI, which tends to be mitigated fordrugs with multiple metabolic pathways (5). For instance,ritonavir increases simvastatin (exclusive CYP3A4 metab-olism) by 100-fold and is contraindicated (5); temporarilypausing simvastatin therapy will not cause clinical harm.Inhibition of CYP3A4 by ritonavir takes several days toresolve, and paused treatment with comedications shouldbe restarted 3 days after the last dose of NMV/r (6).Conversely, no clinically significant DDIs are expectedbetween NMV/r and drugs metabolized by CYP2D6(including most antidepressants) because a low dose ofritonavir weakly inhibits this enzyme (7). Ritonavir alsoinduces several other drug-metabolizing enzymes (7),but induction is unlikely to be clinically relevant becauseit does not reach maximal effect during the short NMV/rtreatment course.Strong enzyme inducers (for example, rifampicin,carbamazepine, enzalutamide, and St. John's wort) cansignificantly reduce NMV/r exposure, potentially jeop-ardizing its efficacy. Because of persistent induction afterwithdrawal of an inducer, DDIs with strong inducers can-not be avoided and require the use of an alternativeCOVID-19 treatment.STRATEGIES FOR MANAGING POTENTIALLYCLINICALLY RELEVANT DDISClinically relevant DDIs with NMV/r can be managedin 4 ways: 1) preemptive pausing of the comedicationtherapy; 2) monitoring or dose adjustment of comedica-tions (not usually feasible); 3) patient counseling withsymptom-driven withdrawal of medications where appro-priate, such as with antihypertensives; or 4) choice of an al-ternative treatment of SARS-CoV-2 infection. Which route ischosen depends on patient characteristics and the risk–benefit balance of modifying treatment of the comorbidcondition. Access to specialist consultation where availableis helpful. In settings where complex management strat-egies are not possible, where DDIs cannot bemitigated, orwhere the effectiveness of NMV/r may be impaired, analternative COVID-19 treatment should be used. TheFigure provides an algorithm for the management ofDDIs with NMV/r. The following sections outline some ofthe key questions to consider when managing DDIs.Can the Comedication BeWithdrawn?Where possible, therapy with contraindicated come-dications should be paused temporarily. If this is notappropriate—for example, if discontinuation poses toomuch risk, such as stopping clopidogrel treatment within6 weeks of coronary stenting (8)—then alternatives to NMV/rshould be considered. For example, a switch from clopidog-rel to prasugrel reverses the deleterious effect of DDIs onplatelet aggregation (9) and, if feasible, should be consid-ered in the 6-week period of highest risk after coronarystenting (8). For other clinical scenarios, a brief reduction inclopidogrel exposuremay be acceptable.This article was published at Annals.org on 1 March 2022.Annals.org Annals of Internal Medicine © 2022 American College of Physicians 1Annals of Internal Medicine IDEAS AND OPINIONSCanDDIManagement AllowNMV/r Treatment?Most DDIs can be managed safely by temporarilywithdrawing the problematic comedication. In some circum-stances, DDIs cannot be prevented by this approach, eitherbecause of persisting effects (for example, residualinduction with carbamazepine or rifampicin) or a verylonghalf-life of the comedication (for example, amiodarone),potentially resulting in inadequate exposure to nirmatrelviror toxic drug levels, respectively. An alternative COVID-19treatment would be considered in such situations.Can Arrangements forMonitoring or DoseAdjustment Be Established?Short-term arrangements for monitoring or dose ad-aptation are challenging to implement. For example,digoxin concentrations are expected to be significantlyincreased by ritonavir through inhibition of P-glycoprotein(10). Management of this DDI is not straightforward,requiring individualization of digoxin dosage or a dosingschedule based on the treatment indication and the patient'srenal function. Without digoxin therapeutic drug monitoring,this interaction requires evaluation of the risk–benefit balance.Although more stringent dosage measures may apply todrugs with a narrow therapeutic index, dosage adjustmentsmay be optional for drugswhoseDDI canbe easilymanaged(such as amlodipine). A special situation exists for patientsalready receiving a drug combination containing the phar-macokinetic booster cobicistat or low-dose ritonavir (that is,patients receiving certain antiretrovirals). For these patients,the additional ritonavir in NMV/r for 5 days is unlikely tocause significant intolerance, and continuation of antiretro-viral therapy is recommended.CHALLENGESNot all potential DDIs result in harms, and prescrib-ers must weigh the risk–benefit balance of co-administra-tion in each case. Additional challenges posed by theneed to isolate and avoid unnecessary attendance athealth care facilities limit our ability to manage theseDDIs. However, the greatest challenges are longstand-ing: incomplete ascertainment of all medications takenand underrecognition of the existence of DDIs. As NMV/ris rolled out across different health care settings, weFigure. Flow diagram to assess management of nirmatrelvir–ritonavir DDIs.Yes YesYesYesEstablish a list with all current comedications (prescribed and over-the-counter drugs, including herbals or illicit substances, notably opioids)Screen DDIs between nirmatrelvir–ritonavir and all comedications (www.covid19–druginteractions.org)No DDI expected   Drug not undergoing CYP      metabolism or transported by      P-gp; e.g., lisinopril, aspirin   Drug metabolized by enzymes      induced by ritonavir; e.g.,      lamotrigine, glipizideWeak DDI: no action needed   Drug metabolized partially by      CYP3A4 with low risk for      adverse event from DDI; e.g.,      methadone, buprenorphine,      codeine, contraceptivesPotential DDI: dose adjust/monitor   Drug requiring potential dose adjustment or      patient counseling about potential DDI;      e.g., amlodipine   Drug requiring complex monitoring; e.g.,      digoxin   Drug requiring evaluation of risk–benefit      balance; e.g., cancer drugsDo not co-administer   Strong inducer   NTI with long half-      lifeDDIs are not manageable(persistent induction ordrug effect); usealternative COVID-19therapy   Sensitive CYP3A4/NTI drug/sensitive P-gp;      e.g., clopidogrel (recent stent), simvastatinCan the drug be withdrawn? Can the drug be withdrawn?No NoNo NoStop comedication therapy Stop comedicationtherapyManageDDIClinicaldecisionConsider anotherCOVID-19 treatmentCan dose of comedication beadjusted or monitoring set up?Adjust dose and/orset up monitoringIs there an alternativecomedication?Switch comedicationProceed with nirmatrelvir–ritonavir treatmentThe inhibitory effect of ritonavir takes several days to resolve. Thus, paused comedication therapy should be restarted 3 d after the last dose of nirmatrel-vir–ritonavir. The same timeline applies for comedications whose dosage has been adjusted during nirmatrelvir–ritonavir treatment. CYP= cytochrome;DDI= drug–drug interaction; NTI = narrow therapeutic index; P-gp= P-glycoprotein.IDEAS AND OPINIONS Management of Drug–Drug Interactions With Nirmatrelvir–Ritonavir2 Annals of Internal Medicine Annals.orgrecommend use of up-to-date resources, such as theLiverpool DDI checker (www.covid19-druginteractions.org).From Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital of Basel and University of Basel, Basel, Switzerland, and Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom (C.M.); Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (D.R.K.); Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, and Department of Pharmacy, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (F.M., A.B.); Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom (S.G., D. Back, S.K.); Divisions of Clinical Pharmacology and Infectious Diseases, School of Medicine, and Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland (C.F.); Chelsea and Westminster Hospital NHS Foundation Trust and London School of Hygiene and Tropical Medicine, London, United Kingdom (A.P.); Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom (M.B.); Mortimer Market Centre, Central and North West London, NHS Foundation Trust, London, United Kingdom (L.W.); and Department of Pharmacy, Radboud University Medical Center, Nijmegen, and Global DDI Solutions, Utrecht, the Netherlands (D. Burger).Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-0281.Corresponding Author: Catia Marzolini, PharmD, PhD, Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital of Basel, Petersgraben 4, 4031 Basel, Switzerland; e-mail, catia.marzolini@usb.ch.Author contributions are available at Annals.org.Ann Intern Med. doi:10.7326/M22-0281References1. U.S. Food and Drug Administration. Coronavirus (COVID-19)update: FDA authorizes first oral antiviral for treatment of COVID-19. 22 December 2021. Accessed at www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19 on 17 January 2022.2. Boffito M, Back D, Gatell JM. Twenty years of boosting antiretro-viral agents: where are we today. AIDS. 2015;29:2229-33. [PMID:26544697] doi:10.1097/QAD.00000000000008003. National Institutes of Health. The COVID-19 Treatment GuidelinesPanel's statement on potential drug-drug interactions between ritonavir-boosted nirmatrelvir (Paxlovid) and concomitant medications. Updated30 December 2021. Accessed at www.covid19treatmentguidelines.nih.gov/therapies/statement-on-paxlovid-drug-drug-interactions on17 January 2022.4. COVID-19 Drug Interactions. University of Liverpool; 2022.Accessed at www.covid19-druginteractions.org on 17 January 2022.5. Stader F, Kinvig H, Battegay M, et al. Analysis of clinical drug-drug interaction data to predict magnitudes of uncharacterized inter-actions between antiretroviral drugs and comedications. AntimicrobAgents Chemother. 2018;62. [PMID: 29686151] doi:10.1128/AAC.00717-186. Stader F, Khoo S, Stoeckle M, et al. Stopping lopinavir/ritonavirin COVID-19 patients: duration of the drug interacting effect[Letter]. J Antimicrob Chemother. 2020;75:3084-3086. [PMID:32556272] doi:10.1093/jac/dkaa2537. Marzolini C, Gibbons S, Khoo S, et al. Cobicistat versus ritonavirboosting and differences in the drug-drug interaction profiles withco-medications. J Antimicrob Chemother. 2016;71:1755-8. [PMID:26945713] doi:10.1093/jac/dkw0328. Valgimigli M, Bueno H, Byrne RA, et al; ESC Scientific DocumentGroup. 2017 ESC focused update on dual antiplatelet therapy in coro-nary artery disease developed in collaboration with EACTS: The TaskForce for dual antiplatelet therapy in coronary artery disease of theEuropean Society of Cardiology (ESC) and of the European Associationfor Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39:213-260. [PMID: 28886622] doi:10.1093/eurheartj/ehx4199. Marsousi N, Daali Y, Fontana P, et al. Impact of boosted antiretrovi-ral therapy on the pharmacokinetics and efficacy of clopidogrel andprasugrel active metabolites. Clin Pharmacokinet. 2018;57:1347-1354.[PMID: 29453687] doi:10.1007/s40262-018-0637-610. Ding R, Tayrouz Y, Riedel KD, et al. Substantial pharmacokineticinteraction between digoxin and ritonavir in healthy volunteers. ClinPharmacol Ther. 2004;76:73-84. [PMID: 15229466]Management of Drug–Drug Interactions With Nirmatrelvir–Ritonavir IDEAS AND OPINIONSAnnals.org Annals of Internal Medicine 3Author Contributions: Conception and design: D. Back, M.Boffito, A. Boyle, D. Burger, C. Flexner, S. Gibbons, S. Khoo, D.R. Kuritzkes, C. Marzolini.Analysis and interpretation of the data: D. Back, A. Boyle, D.Burger, C. Flexner, S. Khoo, F. Marra, C. Marzolini.Drafting of the article: D. Back, D. Burger, C. Flexner, S. Khoo,C. Marzolini, L. Waters.Critical revision for important intellectual content: D. Back, M.Boffito, A. Boyle, D. Burger, C. Flexner, S. Gibbons, S. Khoo, D.R. Kuritzkes, F. Marra, A. Pozniak.Final approval of the article: D. Back, M. Boffito, A. Boyle, D.Burger, C. Flexner, S. Gibbons, S. Khoo, D.R. Kuritzkes, F. Marra,C. Marzolini, A. Pozniak, L. Waters.Administrative, technical, or logistic support: C. Marzolini.Collection and assembly of data: A. Boyle, D. Burger, S.Gibbons, S. Khoo, C. Marzolini.Annals.org Annals of Internal Medicine • Vol. 175 No. 5 • May 2022

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Prescribing Nirmatrelvir-Ritonavir: How to Recognize and Manage Drug-Drug Interactions

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